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Biomedical subjects

L Wouters

Publications and source records attributed to L Wouters.

At least 55 records · Page 3Linked to original sources
PubMed1991

Effects of R 56,865, a preventer of cellular calcium overload, on left ventricular diastolic properties during pacing-induced ischemia in dogs.

The effects of R 56,865, a compound with unusual calcium antagonistic properties, on altered left ventricular (LV) diastolic properties were studied during pacing-induced ischemia in dogs with coronary stenosis. Severe coronary artery stenosis was produced on both the left anterior descending (LAD) and circumflex (Cx) coronary arteries in anesthetized beta-blocked dogs. The right atrium was paced at 200 beats/min for 3 min. In the post-pacing period and before drug intervention, the most characteristic observation was a significant increase in LV end-diastolic pressure (LVEDP) and in the time constant of (tau) LV pressure decrease; after return of LV hemodynamics to baseline values (15 min), R 56,865 (0.16 mg.kg-1) or solvent (control) was injected and four subsequent pacing runs were performed at 30-min intervals. In the postpacing period of these four subsequent runs, there was a steep increase in LVEDP and tau-values while HR returned more slowly to baseline values. After R 56,865 infusion, the increase in LVEDP and tau-values was significantly lower than in the pretreatment run and all LVEDP values were significantly lower than in the control group. We conclude that R 56,865 effectively attenuates ischemia-induced changes in LV diastolic stiffness.

Animals↗
PubMed1991

Nebivolol increases survival in cardiomyopathic hamsters with congestive heart failure.

The genetically inbred cardiomyopathic Syrian hamster provides a valuable model of congestive cardiomyopathy: myocytolytic necrosis at 30-50 days of age is followed by cardiac hypertrophy at 150-250 days, and finally by congestive failure and death at 250-350 days. Successful drug treatment has been reported in the prenecrotic stage, but not when started during congestive failure. The present study evaluated survival of the cardiomyopathic hamster treated with the new beta-adrenoceptor blocker nebivolol, which was initiated during congestive failure. Fifty animals (BIO82.62, either sex, age 200 days) were acclimated to an environmentally controlled room for 20 days, receiving food and water ad libitum; seven hamsters died, indicating development of congestive failure. The remaining animals were then randomly assigned to one of three groups: 15 animals received control food; food for the others was supplemented with nebivolol, yielding a daily intake of either 0.1 mg/kg (n = 14) or 1 mg/kg (n = 14). At the lower nebivolol dose, death rate was unaltered in comparison with controls. However, at 1 mg/kg, survival was markedly improved (p = 0.042). Nebivolol treatment, started during congestive failure, thus significantly delays mortality in the cardiomyopathic hamster.

Adrenergic beta-Antagonists↗
PubMed1991

Differential effects of thromboxane A2 synthase inhibition, singly or combined with thromboxane A2/prostaglandin endoperoxide receptor antagonism, on occlusive thrombosis elicited by endothelial cell injury or by deep vascular damage in canine coronary arteries.

In open-chest dogs, cyclic flow reductions (CFRs, 5.1-6.6/hr in controls; n = 24) caused by platelet deposition/dislodgment at sites of endothelial cell injury in critically stenosed left anterior descending coronary arteries (59% flow reduction) were attenuated to the same extent either by single thromboxane A2 (TXA2) synthase inhibition (0.31 mg/kg i.v. ridogrel; CFR, 0.16 +/- 0.16/hr; n = 6; p less than 0.05) or by a comparatively modest degree of TXA2/prostaglandin endoperoxide receptor antagonism on top of TXA2 synthase inhibition (5 mg/kg i.v. ridogrel; CFR, 0.22 +/- 0.1/hr; n = 10; p less than 0.05). By contrast, occlusive thrombosis on deep vascular damage elicited by intraluminal stimulation (150-microA anodal constant current) in nonpreconstricted canine coronary arteries (time to occlusion, 237.1 +/- 13.9 minutes; n = 7; incidence of occlusion within 300 minutes, six of seven experiments) was not affected by platelet cyclooxygenase inhibition (5 mg/kg i.v. acetylsalicylic acid; n = 7), single TXA2 synthase inhibition (1.25 mg/kg i.v. ridogrel; n = 7), or single TXA2/prostaglandin endoperoxide receptor antagonism (10 mg/kg + 10 mg/kg/hr i.v. sulotroban for 300 minutes; n = 5). However, such an occlusive thrombus formation was significantly reduced by combined TXA2 synthase/prostaglandin endoperoxide receptor inhibition (5 mg/kg i.v. ridogrel; time to occlusion greater than 300 minutes, n = 7; incidence of occlusion within 300 minutes, one of seven experiments; p less than 0.05). This study reveals 1) a differential efficacy of TXA2 synthase inhibition, singly or combined with TXA2/prostaglandin endoperoxide receptor antagonism, depending on the extent of the vessel wall lesion triggering thrombosis and the size of the thrombus required to obstruct the vascular lumen and 2) a significant synergism in preventing occlusive thrombosis of extensively damaged coronary arteries between strong TXA2 synthase inhibition and comparatively modest TXA2/prostaglandin endoperoxide receptor antagonism with ridogrel.

Animals↗
PubMed1991

The effects of saperconazole on the morphology of Candida albicans, Pityrosporum ovale and Trichophyton rubrum in vitro.

Fungal cultures were incubated for various periods of time with saperconazole at concentrations ranging from 10(-10) to 10(-5) M: Candida albicans (4 and 24 h), Pityrosporum ovale (2 and 7 days), and Trichophyton rubrum (1, 2, 3, 7 and 14 days). At the end of the incubation period, fungal morphology was compared with that of control cultures by transmission and scanning electron microscopy. In all three species, major ultrastructural changes were seen from concentrations of 10(-8) to 10(-7) M saperconazole onwards, depending on the species and time of incubation. The main changes were inhibition of hyphal outgrowth (C. albicans), abortive hyphal outgrowth (T. rubrum) and deposition of electron-dense vesicles in a thickened cell wall (C. albicans, T. rubrum). In P. ovale, a direct, necrotizing action was seen without concomitant wall changes.

Antifungal Agents↗
PubMed1990

Effects of beta-adrenoceptor antagonists on cardiac function in ischemic-reperfused myocardium of the isolated working rabbit heart.

The effects of beta-adrenoceptor antagonists (dl-nebivolol, atenolol and propranolol) and of 1-nebivolol on cardiodynamics and mitochondrial oxidative phosphorylation were studied in the isolated working rabbit heart subjected to normothermic global ischemia, followed, in some cases, by reperfusion. The hearts were pretreated with the different drugs (0.32 mg/l) 30 min before the start of ischemia, dl-Nebivolol and propranolol provided protection for both cardiodynamic and mitochondrial functions, as did l-nebivolol, which lacks beta-adrenoceptor blocking properties, while atenolol failed to protect mechanical activity and cardiac mitochondria against the effects of ischemia and post-ischemic reperfusion. Catecholamine depletion with reserpine did not have a beneficial effect on the recovery of cardiodynamic and mitochondrial function during post-ischemic reperfusion. It is concluded that the beneficial effects of beta-blockers on the ischemic and reperfused myocardium can not be explained by a specific beta-blocking action alone.

Adrenergic beta-Antagonists↗
PubMed1990

The l-enantiomer of nebivolol potentiates the blood pressure lowering effect of the d-enantiomer.

In this study the effect of l-nebivolol on the blood pressure lowering action of d-nebivolol was investigated after intraperitoneal administration of the drugs to spontaneously hypertensive rats. Doses of l-nebivolol which did not affect blood pressure when given alone potentiated the decrease in systolic and diastolic blood pressure induced by 1.25 mg.kg-1 d-nebivolol. The potentiating effect of l-nebivolol was seen at doses higher than 0.16 mg.kg-1. At 1.25 mg.kg-1 d-nebivolol significantly reduced the heart rate, an effect which was not potentiated by l-nebivolol in doses up to 1.25 mg.kg-1. Higher doses of l-nebivolol (2.5 and 5.0 mg.kg-1) in combination with 1.25 mg.kg-1 d-nebivolol not only lowered the blood pressure further, but also significantly reduced the heart rate; thus at these doses the enantiomers together exerted more pronounced beta 1-adrenoceptor blocking properties. This is probably disadvantageous, because d,l-nebivolol has been shown to decrease arterial blood pressure in hypertensive patients and animals before it reaches its maximal beta 1-adrenoceptor blocking effect. Therefore, the racemic mixture of 50% d-nebivolol and 50% l-nebivolol seems to contain the two compounds in near optimal proportions for an antihypertensive effect.

Adrenergic beta-Antagonists↗
PubMed1990

Antitumoral effects of R 75251 on the growth of transplantable R3327 prostatic adenocarcinoma in rats.

The antitumoral activity of a novel imidazole derivative, R 75,251, has been studied in the androgen-dependent R3327G Dunning prostate adenocarcinoma grafted subcutaneously in syngeneic rats. Dietary application resulting approximately in dose levels of 80, 120, and 160 mg/kg reduced tumor weight by 66, 81, and 79%, respectively. This effect was not significantly different from that measured after castration (-82%). In intact animals, however, serum testosterone levels were almost not affected by R 75,251 treatment while LH levels rose two- to threefold. In castrated rats a tenfold increase in LH was observed. Moreover, prostate and seminal vesicles weights decreased much less after R 75,251 treatment than after castration. In castrated animals, treatment with R 75,251 induced a slight, non-significant reduction in tumor weight (-36%) compared with castration alone. In castrated animals, tumor growth was restored by exogenous administration of testosterone. In such animals R 75,251 also significantly reduced tumor weight by 57%. Similar results were obtained with Dunning R3327G prostate adenocarcinoma grafted beneath the renal capsule in male syngeneic rats receiving twice daily orally by gavage a dose of 80 mg/kg of R 75,251. These data suggest that R 75,251 exerts an antitumoral effect independent of its inhibition of androgen biosynthesis.

Adenocarcinoma↗
PubMed1990

Deceleration in cumulative food intake curves, changes in body temperature and diet-induced thermogenesis.

In order to assess the relationship between the shape of the cumulative food intake curve and a reflection of internal processes, eating behaviour, postprandial thermogenesis, and skin and core temperature of normal weight restrained and unrestrained eating women and of obese restrained eating women were recorded during four-course solid food lunches, eaten in a laboratory setting (respiration chamber) at a constant ambient temperature of 22 degrees C. The skin temperature (upper arm, upper leg, liver proximity) and core temperature were measured constantly from one hour prior to until two hours after the lunch. Normal weight unrestrained eaters displayed decelerated cumulative food intake curves and an increase in the liver temperature data of 0.8-1.5 degrees C, from the beginning of the meal onwards, remaining high until 60-90 minutes after the meal was consumed. The postprandial thermogenesis of normal weight unrestrained eaters was on average 8.1 +/- 1.3%, calculated over two and a half hours from the beginning of the meal. Overweight and normal weight restrained eaters displayed linear cumulative food intake curves, almost no changes in skin and core temperatures and a postprandial thermogenesis of 4.2 +/- 0.3% and 4.8 +/- 0.7%, calculated over two and a half hours from the beginning of the meal onwards. In conclusion, deceleration in cumulative food intake curves is positively correlated with a temperature increase in the skin in the proximity of the liver, and with postprandial thermogenesis.

Adult↗
PubMed1990

5-Hydroxytryptamine and arachidonic acid metabolites modulate extensive platelet activation induced by collagen in cats in vivo.

1. The pathways contributing to the platelet adhesion/aggregation reaction elicited by collagen microfibrils, administered to cats in vivo, were analysed. 2. The intra-aortic infusion of collagen (100 micrograms kg-1 in 1 min) caused an extensive activation of platelets, as evidenced by the time-dependent drop of free platelet numbers in whole blood, and the increases of 5-hydroxyindoles (5-HI), 5-hydroxytryptamine (5-HT) and thromboxane B2 (TXB2) levels in plasma, prepared from effluent venous blood sampled from the inferior caval vein. 3. 5-HT2 receptor blockade with ketanserin (0.63 mg kg-1 i.v., 10 min) and cyclo-oxygenase inhibition with aspirin (10 mg kg-1 i.v., 10 min) slightly attenuated the peak reduction of free platelets in whole blood in response to collagen without affecting changes in plasma 5-HI. Aspirin, but not ketanserin, reduced the collagen-induced changes in plasma TXB2, prostaglandin E2 (PGE2) and 6K-PGF1 alpha. 4. Dual TXA2 synthetase inhibition/TXA2-prostaglandin endoperoxide receptor antagonism with ridogrel (5 mg kg-1 i.v., 10 min) halved the drop in free platelets, reduced the release of platelet 5-HI, inhibited the increase in plasma TXB2 and elevated that of 6K-PGF1 alpha and PGE2 in response to collagen. 5. Combined treatment with ketanserin and aspirin reduced the collagen-induced drop of free platelets and the release of platelet 5-HI to a similar extent as ridogrel alone; plasma prostanoids were affected as with aspirin alone. 6. Combined administration of ketanserin and ridogrel virtually eliminated the collagen-induced platelet adhesion/aggregation response and release of 5-HI; prostanoids were affected as with ridogrel alone. 6. Combined administration of ketanserin and ridogrel virtually eliminated the collagen-induced platelet adhesion/aggregation response and release of 5-HI; prostanoids were affected as with ridogrel alone. 7. The results indicate that the interplay between 5-HT and arachidonic acid metabolites is causally involved in the platelet reaction to activation induced by collagen in cats in vivo.

Animals↗
PubMed1990

Two groups of rhinoviruses revealed by a panel of antiviral compounds present sequence divergence and differential pathogenicity.

A variety of chemically different compounds inhibit the replication of several serotypes of rhinoviruses (common-cold viruses). We noticed that one of these antiviral compounds, WIN 51711, had an antiviral spectrum clearly distinctive from a consensus spectrum or other capsid-binding compounds, although all of them were shown to share the same binding site. A systematic evaluation of all known rhinovirus capsid-binding compounds against all serotyped rhinoviruses was therefore initiated. Multivariate analysis of the results revealed the existence of two groups of rhinoviruses, which we will call antiviral groups A and B. The differential sensitivity of members of these groups to antiviral compounds suggests the existence of a dimorphic binding site. The antiviral groups turned out to be a reflection of a divergence of rhinovirus serotypes on a much broader level. Similarities in antiviral spectra were highly correlated with sequence similarities, not only of amino acids lining the antiviral compound-binding-site, but also of amino acids of the whole VP1 protein. Furthermore, analysis of epidemiological data indicated that group B rhinoviruses produced more than twice as many clinical infections per serotype than group A rhinoviruses did. Rhinoviruses belonging to the minor receptor group were without exception all computed to lie in the same region of antiviral group B.

Amino Acid Sequence↗
PubMed1989

Influence of the synthetic microtubule inhibitor erbulozole (P.I.N.N.) (R 55 104), a new tubulozole congener, and gamma irradiation on murine tumors in vivo.

Erbulozole (P.I.N.N.) (R 55 104) is a more water soluble congener of the synthetic microtubule inhibitor tubulozole (R 46 846) exhibiting a reversible antimicrotubular activity in vitro at a dose (1.56 x 10(-8) M) which is at least 10-fold lower. The compound also has an antiinvasive potential and shows antitumoral effects both in vitro and in vivo when administered appropriately. Eighty mg/kg R 55 104, given orally 6 h before or 3 h after radiotherapy, displays a prominent interactive effect with 10 Gy gamma irradiation in subcutaneous murine tumors which is similar to 160 mg/kg tubulozole administered 6 h before 10 Gy. The enhancing effect is also observed in a clinically relevant radiation dose fractionation schedule whereby eight fractions of 2 Gy each were pretreated 2 h before with 40 mg/kg R 55 104. Further study of this radiochemotherapeutic combination may lead to new clinical applications.

Animals↗
PubMed1989

Interaction between the microtubule inhibitor tubulozole and gamma-irradiation in murine tumors in vivo.

The combined effect of the microtubule inhibitor tubulozole and gamma-irradiation has been investigated in vivo in subcutaneous MO4 fibrosarcomas and Lewis Lung carcinomas. A marked interactive effect on tumor growth was observed when 160 mg/kg tubulozole was orally administered before the tumors were treated with 10 Gy radiation. Dose dependency and optimal effect were obtained on tumor growth of MO4 tumor bearing animals when the drug treatment was given 6 hr prior to the irradiation. The optimal pretreatment time coincided with the time at which a peak mitotic index in the tumor tissue was observed. An enhancing effect is also noticed at other doses of radiation in MO4 tumors pretreated 6 hr before with 160 mg/kg tubulozole. The interactive effect is maintained in a clinically relevant dose fractionation schedule whereby 8 fractions of 2 Gy each were pretreated 6 hr before with 80 mg/kg tubulozole. Tubulozole-T, the stereo-isomer of tubulozole, neither exhibits any antimicrotubular action nor exerts an antitumoral effect on its own or in combination with gamma-irradiation. The possible mechanisms of interaction between tubulozole and gamma-irradiation in tumor tissue are discussed.

Animals↗
PubMed1987

Radioactive colloidal gold as a tool to quantify extravasation of macromolecules in the rat cremaster muscle.

Since previously described simple methods were too insensitive to quantify the extent of microvascular permeability increase in the rat cremaster muscle, we applied a new quantitative technique using radioactive colloidal gold (198Au) as the macromolecular tracer. Dose-response effects on microvascular permeability were found with increasing doses of subscrotally injected serotonin or histamine. The presence of colloidal gold particles in the subendothelial space of the postcapillary venules, as verified ultrastructurally, indicated endothelial permeation of the tracer macromolecules. The increased permeability elicited by serotonin was inhibited in a dose-dependent way by serotonin receptor antagonists (potency: methysergide greater than or equal to ketanserin = ritanserin greater than cinanserin), suggesting the presence of functional S2-serotonergic receptors on postcapillary venular endothelial cells. A dose-related inhibition of the histamine-induced extravasation was seen with the H1 antagonists astemizole and azatidine (astemizole greater than azatidine); the H2 antagonists cimetidine and ranitidine had no inhibitory effect. The radioactive colloidal gold technique is a sensitive and reliable tool for pharmacological experiments aimed at investigating the extravasation phenomenon in small tissue samples such as the rat cremaster muscle.

Animals↗
PubMed1986

The human umbilical vein graft in below-knee femoropopliteal and femorotibial surgery: an eight year experience.

The authors present a series of 175 femoropopliteal (below-knee) and 65 femorotibial reconstructions with the human umbilical vein (HUV) graft performed over an eight year period. With a mean follow-up of 36.7 months (range one month to 84 months) the early patency rate of 89% decreased to 54% after five years. Long-term patency was found to be primarily related to the location of the distal anastomosis and the quality of the outflow, showing a statistically significant decrease after repeat revascularization. Early thrombosis, even in the absence of a technical failure and late aneurysmal degeneration remain the major problems associated with the use of the HUV graft. It is therefore recommended that these reconstructions be preserved for patients with advanced ischemia or a limited life-expectancy.

Adult↗
PubMed1985

Effects of etomidate on cortisol biosynthesis in isolated guinea-pig adrenal cells: comparison with metyrapone.

The effects of the iv hypnotic etomidate on cortisol biosynthesis have been investigated in short term incubations of dispersed guinea-pig adrenal cells and were compared with those produced by metyrapone. Fifty percent inhibition of cortisol output was obtained at a final medium concentration of 3.5 10(-8) M (basal), 2.8 10(-8) M (ACTH-stimulated) for etomidate and of 5.10(-7) M (stimulated) for metyrapone. In the presence of etomidate, 11-deoxycortisol at 5.10(-8) M reached a peak value of 244 +/- 11% of control (mean +/- SE, n = 7). 17 alpha-Hydroxyprogesterone and progesterone were not significantly affected up to 10(-7) M, but at higher concentrations, all three precursors fell under their control values. Metyrapone induced a progressive rise of 11-deoxycortisol, from 10(-7) M upwards, to a maximum level at 10(-5) M (210 +/- 15% of control, mean +/- SE, n = 5). 17-Hydroxyprogesterone and progesterone concentrations were not significantly modified by metyrapone. The less active hypnotic L-enantiomer of etomidate had almost no inhibitory effect on cortisol production. The results obtained so far suggest that etomidate is a potent inhibitor of the mitochondrial cytochrome P-450 enzymes of the adrenal cortex, mainly the 11 beta-hydroxylase. At higher dose the cholesterol side-chain cleavage enzyme system seemed also to be affected.

17-alpha-Hydroxyprogesterone↗
PubMed1985

Thromboxane A2-induced vascular endothelial cell damage and respiratory smooth muscle cell contraction: inhibition by flunarizine, a Ca2+-overload blocker.

The fast intravenous injection of arachidonic acid (AA) in mice produces, in a dose-related way, mortality due to respiratory distress. Upon electron microscopical examination an extensive oedematous damage of the capillary endothelium was found; thrombotic platelet obstructions were present in a minority of pulmonary capillaries only. Protection against this toxic AA-effect is obtained with inhibitors of fatty acid cyclo-oxygenase and of thromboxane (TXA2) synthetase, suggesting involvement of TXA2 as a causative mediator. The Ca2+-entry blockers flunarizine, niludipine and nimodipine, not affecting TXA2 synthesis by murine platelets, also provide protection, but not the antiplatelet drugs ticlopidine, dipyridamole or suloctidil; thrombocytopenia induced by busulphan does not affect the AA-induced mortality nor the protection obtained with flunarizine. Platelet-independent bronchoconstriction induced by AA in guinea-pigs is also inhibited by flunarizine. This study suggests that the AA-induced mortality test reflects pulmonary conversion of AA to TXA2 producing endothelial cell damage and respiratory smooth muscle cell contraction rather than a thrombotic phenomenon. The protective effect of flunarizine against TXA2 induced changes in vivo may contribute to its effectiveness in particular hypoxic conditions associated with liberation of AA.

Animals↗
PubMed1985

Cardiovascular effects of ketanserin in closed-chest anesthetized dogs.

The cardiovascular effects of the selective 5 HT2-serotonergic antagonist Ketanserin (cumulative doses of 0.01, 0.04, 0.16, 0.64 and 2.5 mg.kg-1 i.v. at 30 min intervals) were investigated in closed-chest, anesthetized dogs with spontaneously beating hearts (n = 7) and in dogs with a fixed heart rate (n = 7). Besides, the effects of Ketanserin (0.04 mg.kg-1 i.v.) during serotonin infusion (median: 20 micrograms kg-1.min-1 i.v.) were studied (n = 7). Ketanserin, starting at 0.04 mg.kg-1, lowers arterial blood pressure through a decrease in systemic vascular resistance. The increase in heart rate after the injection of 0.16 mg.kg-1 and higher doses is likely reflexogenic in nature and secondary to the decrease in systemic vascular resistance. Ketanserin also induces a positive inotropic effect, starting at a dose of 0.16 mg.kg-1 as indicated by the increase in LV dP/dt max, LV dP/dt max/P and maximum aortic blood flow velocity at constant heart rate and in the presence of no change or a slight decrease in left ventricular end-diastolic pressure. Whether this is an intrinsic property of the compound remains subject to further investigation. Except for the increase in the variables related to left ventricular function, Ketanserin (0.04 mg.kg-1) blocks the serotonin induced circulatory and respiratory changes. The inhibition of serotonin induced pulmonary hypertension and bronchoconstriction was especially marked. The positive inotropic properties of serotonin were not blocked by Ketanserin, suggesting that this property of the amine is not 5 HT2-receptor mediated.

Anesthesia↗